Adolescent offspring of parents with bipolar disorder, particularly those with prominent depressive symptoms, have an elevated risk of developing mania, and by definition bipolar I disorder, compared with the general population. However, medications that are commonly used to treat depressive symptoms may accelerate the onset of mania or hypomania. Therefore, studies evaluating the efficacy, safety, and tolerability of potential treatments for depressive symptoms in adolescents with a bipolar parent are necessary, and may lead to early intervention, and ultimately prevention, strategies for incipient manic and hypomanic episodes. Preclinical and clinical evidence suggests that omega-3 fatty acid deficiency may represent a preventable risk factor for developing bipolar disorder. Indeed, findings from preliminary placebo-controlled trials indicate that omega-3 fatty acid supplementation reduces mood symptom severity in youth and adults with mood disorders. Additionally, postmortem studies reveal significant omega-3 fatty acid deficits in the prefrontal cortex of young bipolar patients. Recent neuroimaging studies indicate that symptoms of bipolar disorder may arise from dysfunction within the anterior limbic network, which includes the ventrolateral prefrontal and anterior cingulate cortices. Specifically, proton magnetic resonance spectroscopy (1H MRS) studies reveal that adolescents with and at high risk for developing bipolar disorder exhibit excessive glutamate and myo-inositol and decreased N- acetyl aspartate levels, suggesting that hypermetabolism may underlie the disruption in anterior limbic brain regions. These neurochemical changes may be useful biomarkers of treatment effects. With these considerations in mind, the goals of this study are: 1) To collect pilot data regarding the efficacy, safety, and tolerability of omega-3 fatty acid supplementation for the treatment of adolescents with active depressive symptoms and a high risk for developing mania (i.e. they have a bipolar parent and meet DSM-IV-TR criteria for major depressive disorder), and 2) To use 1H MRS (i.e. prefrontal neurochemistry) and red blood cell (RBC) omega-3 fatty acid levels to examine potential mediators of treatment response to omega-3 fatty acids in adolescents with a high risk for mania. To accomplish these aims, a total of 60 adolescents (ages 12-21 years) with active depressive symptoms and significant risk factors for developing mania will be randomized to treatment with omega-3 fatty acids or placebo for 12 weeks. The aims of this application are consistent with those of the NIMH R34 grant mechanism;"pilot testing of new or adapted interventions" and "development of novel interventions to target specific risk factors for psychopathology or etiologic factors identified through neuroscience research". Additionally, the proposed study will capitalize on the infrastructure of the NIMH supported Center for Interventions Development and Applied Research (CIDAR) grant;the University of Cincinnati Bipolar Disorder Imaging and Treatment Research Center (BITREC, P50MH077138). Public Health Relevance: Evidence-based treatments are urgently needed for mood disorders in youth at high risk for developing bipolar disorder. This proposal will combine novel neuroimaging techniques with a placebo-controlled double-bind treatment trial in order to examine the neurophysiologic and therapeutic effects of chronic omega-3 fatty acid supplementation in adolescents at high risk for developing bipolar disorder, as an initial step to establish early intervention and prevention strategies.